20-45895143-C-T

Variant names:

• chr20-45895143-C-T
• rs4608591
• ENST00000484855.4:n.1148C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000484855.4(CTSA):​n.1148C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 1,613,544 control chromosomes in the GnomAD database, including 339,194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (32954 hom., cov: 30)
  • Exomes 𝑓: 0.65 (306240 hom.)
• Consequence: CTSA ENST00000484855.4 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.592
• Publications: 23 publications found

Genes affected

CTSA (HGNC:9251): (cathepsin A) This gene encodes a member of the peptidase S10 family of serine carboxypeptidases. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate two chains that comprise the heterodimeric active enzyme. This enzyme possesses deamidase, esterase and carboxypeptidase activities and acts as a scaffold in the lysosomal multienzyme complex. Mutations in this gene are associated with galactosialidosis. [provided by RefSeq, Nov 2015]

CTSA Gene-Disease associations (from GenCC):

• galactosialidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, ClinGen, Illumina

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 20-45895143-C-T is Benign according to our data. Variant chr20-45895143-C-T is described in ClinVar as Benign. ClinVar VariationId is 338538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000484855.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSA	NM_000308.4	MANE Select	c.1088+10C>T		intron	N/A	NP_000299.3
	CTSA	NM_001127695.3		c.1088+10C>T		intron	N/A	NP_001121167.1
	CTSA	NM_001167594.3		c.1037+10C>T		intron	N/A	NP_001161066.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSA	ENST00000484855.4	TSL:1	n.1148C>T		non_coding_transcript_exon	Exon 11 of 12
	CTSA	ENST00000646241.3	MANE Select	c.1088+10C>T		intron	N/A	ENSP00000493613.2
	CTSA	ENST00000372484.8	TSL:1	c.1142+10C>T		intron	N/A	ENSP00000361562.3

Frequencies

GnomAD3 genomes AF: 0.658 AC: 99810 AN: 151726 Hom.: 32919 Cov.: 30

Gnomad AFR AF: 0.670

Gnomad AMI AF: 0.592

Gnomad AMR AF: 0.721

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.694

Gnomad SAS AF: 0.681

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.633

Gnomad OTH AF: 0.642

GnomAD2 exomes AF: 0.665 AC: 166930 AN: 251128 AF XY: 0.659

Gnomad AFR exome AF: 0.669

Gnomad AMR exome AF: 0.779

Gnomad ASJ exome AF: 0.512

Gnomad EAS exome AF: 0.690

Gnomad FIN exome AF: 0.690

Gnomad NFE exome AF: 0.632

Gnomad OTH exome AF: 0.644

GnomAD4 exome AF: 0.646 AC: 944208 AN: 1461700 Hom.: 306240 Cov.: 58 AF XY: 0.646 AC XY: 469418 AN XY: 727142

African (AFR) AF: 0.666 AC: 22301 AN: 33476

American (AMR) AF: 0.773 AC: 34561 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 13629 AN: 26134

East Asian (EAS) AF: 0.726 AC: 28837 AN: 39696

South Asian (SAS) AF: 0.677 AC: 58425 AN: 86254

European-Finnish (FIN) AF: 0.690 AC: 36808 AN: 53352

Middle Eastern (MID) AF: 0.580 AC: 3345 AN: 5768

European-Non Finnish (NFE) AF: 0.637 AC: 707828 AN: 1111912

Other (OTH) AF: 0.637 AC: 38474 AN: 60386

GnomAD4 genome AF: 0.658 AC: 99903 AN: 151844 Hom.: 32954 Cov.: 30 AF XY: 0.662 AC XY: 49110 AN XY: 74200

African (AFR) AF: 0.670 AC: 27718 AN: 41388

American (AMR) AF: 0.721 AC: 10998 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1851 AN: 3470

East Asian (EAS) AF: 0.694 AC: 3572 AN: 5150

South Asian (SAS) AF: 0.681 AC: 3280 AN: 4814

European-Finnish (FIN) AF: 0.702 AC: 7390 AN: 10534

Middle Eastern (MID) AF: 0.599 AC: 175 AN: 292

European-Non Finnish (NFE) AF: 0.633 AC: 43018 AN: 67930

Other (OTH) AF: 0.645 AC: 1362 AN: 2112

Alfa AF: 0.640 Hom.: 82454

Bravo AF: 0.658

Asia WGS AF: 0.716 AC: 2490 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Oct 19, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Combined deficiency of sialidase AND beta galactosidase Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 66% of total chromosomes in ExAC

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.3
DANN	Benign	0.60
PhyloP100		-0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4608591; hg19: chr20-44523782; COSMIC: COSV107206972; COSMIC: COSV107206972;